Approval lag and loss for biologic-device combination products in Japan and the United States.

Introduction: The market for drug delivery devices (DDDs), including combination products that integrate pharmaceuticals and medical devices, has expanded rapidly with the increasing use of biopharmaceuticals and growing adoption of self-administration. However, the extent and causes of approval lag and approval loss for device presentations, defined as presentations approved in one country but unavailable in the other, have not been systematically evaluated between Japan and the United States. Methods: We analyzed approvals of biopharmaceuticals in various device presentations, including prefilled syringes (PFS), autoinjectors, multidose pen injectors, on-body injectors (OBIs), and cartridge formulations, using the Pharmaceuticals and Medical Devices Agency (PMDA) and U.S. Food and Drug Administration (FDA) databases from 2000 to 2025. Results: Among 176 biopharmaceutical products approved in the United States, 16% were not approved in Japan. However, most cases were attributable to approval loss by drug, reflecting products whose active substances were not approved for the Japanese market, rather than approval loss by device presentation. Although median approval lag tended to vary across device presentations, with multidose pen injectors and cartridge presentations showing median delays exceeding approximately two years and autoinjectors showing the shortest lag at approximately 10 months, these differences were not statistically significant. Statistical analyses using Pearson's chi-square, Fisher's exact, and Kruskal-Wallis tests showed no significant differences in device presentation approval between Japan and the United States after excluding products lacking active substance approval in either country ( Discussion: In the United States, multiple device presentations were often approved simultaneously, whereas Japan more frequently adopted a stepwise approval approach. Differences in the regulatory scope of combination products and co-packaging requirements also contributed to country- specific packaging, potentially prolonging pre-approval preparation and increasing supply chain complexity. Overall, regulatory approval discrepancies between Japan and the United States were driven primarily by drug loss rather than device presentation loss. Accelerating drug approval, promoting simultaneous development of multiple device presentations, and enhancing regulatory harmonization for combination products may reduce approval lag by device presentation and improve patient access.